Authors' Affiliations: Division of Clinical Oncology, Department of Medicine; Research Unit: Genetic Epidemiology and Pharmacogenetics, Division of Clinical Oncology; Institute of Pathology; Clinical Institute of Medical and Laboratory Diagnostics, Medical University of Graz; Department of Pathology, General Hospital Graz West, Graz; Department of Pathology, General Hospital of Leoben, Leoben, Austria; and Department of Medical Oncology, University Hospital Zuerich, Zuerich, Switzerland.
Clin Cancer Res. 2014 Mar 15;20(6):1687-97. doi: 10.1158/1078-0432.CCR-13-1517. Epub 2014 Jan 27.
Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma.
A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5'-exonuclease assays.
In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G>C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR = 2.35; confidence interval (95% CI), 1.48-3.74; P < 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural-invasion (HR = 2.43; CI 95%, 1.52-3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR = 3.21; CI 95%, 1.59-6.49; P = 0.001), in contrast with patients with adjuvant chemotherapy (HR = 0.82; CI 95%, 0.35-1.95; P = 0.657). When the subgroup of patients with "high-risk" GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5-fluorouracil-based chemotherapy could be found.
This is the first study identifying GLI1 rs2228226 G>C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings.
越来越多的证据表明，Wnt、Notch 和 Hedgehog 通路中的种系变异与结肠癌的进展和转移有关。我们研究了 Wnt、Notch 和 Hedgehog 通路基因的综合面板中的种系多态性，以预测 II 期和 III 期结肠癌患者的复发时间 (TTR) 和总生存期。
本回顾性研究共纳入 742 例连续收集的 II 期和 III 期结肠癌患者。通过 TaqMan 5'-exonuclease 分析，对 Wnt、Notch 和 Hedgehog 通路基因 (SFRP、DKK2 和 3、AXIN2、APC、MYC、TCF7L2、NOTCH2 和 GLI1) 中的 18 种种系多态性进行了基因组 DNA 分析。
在单因素分析中，在调整多重检验后，GLI1 rs2228226 G>C 的纯合突变等位基因在隐性遗传模型中与 TTR 降低显著相关 [HR = 2.35；置信区间 (95%CI)，1.48-3.74；P < 0.001]，并且在包括临床分期、淋巴血管、血管和神经周围浸润的多因素分析中仍然显著 (HR = 2.43；CI 95%，1.52-3.87；P < 0.001)。在亚分析中，这种相关性仅限于仅接受手术的患者 (HR = 3.21；CI 95%，1.59-6.49；P = 0.001)，而与接受辅助化疗的患者不同 (HR = 0.82；CI 95%，0.35-1.95；P = 0.657)。当分析 GLI1 rs2228226 具有“高风险”C/C 基因型的患者亚组时，发现辅助 5-氟尿嘧啶为基础的化疗没有获益。
这是第一项确定 GLI1 rs2228226 G>C 作为 II 期和 III 期结肠癌患者独立预后标志物的研究。需要前瞻性研究来验证我们的发现。
